Derivative of nicotinic acid with amines

ABSTRACT

A novel thiazolidide ester of nicotinic acid is disclosed having the formula: ##STR1## The compound has the useful pharmacological activity of lowering cholesterol, free fatty acid and triglyceride plasma levels in cases of malfunctioning lipid metabolism. 
     A synthesis of the compound from nicotinoyl chloride hydrochloride or nicotinic acid is described as well as modes for the administration of the compound.

RELATED APPLICATIONS

This application is a Continuation-in-Part of patent application Ser.No. 451,696 filed Mar. 15, 1974 and herewith abandoned.

FIELD OF THE INVENTION

This invention relates to the novel nicotinic acid ester, thethiazolidide-4-carboxylic ethyl ester of nicotinic acid and moreparticularly to its synthesis, utility and modes for its usefuladministration.

THE INVENTION

The compound: Thiazolidide-4-carboxylic ethyl ester of nicontinic acidhaving the formula: ##STR2## and its pharmaceutically acceptable saltshave useful pharmacological activity related to lipid metabolism andindicated therapeutic activity in dislipidaemias.

DETAILED DESCRIPTION OF THE INVENTION

The invention above will be more fully described by the appendedexamples and by references to the drawing where:

FIG. 1 shows the effect of the compound of the invention on lipidmetabolism (FFA and triglycerides) in fasted rats.

FIG. 2 shows the effect of the compound of the invention onnor-adrenaline and 3'5-AMPc-treated adipose tissue.

The compound is prepared by reacting nicotinyl chloride hydrochloride ornicotinic acid esters with 4-thiazolidine carboxylic acid - ethyl esterin an anhydrous organic solvent inert to the reactants. Preferably thereaction is carried out in anhydrous chloroform, dioxane,tetrahydrofurane, (THF), N,N-dimethyl formamide (DMF). Chloroform ispreferred. Part of the solvent medium may be an anhydrous proton orhaloacid acceptor. Among such anhydrous acceptors are triethylamine,other trialkylamines, pyridine etc.

The reaction proceeds at temperatures between 15° and 90° C. Preferablythe reaction provides a purer product in best yield at temperatures inthe range 20°- 30° C.

The product is purified by recrystallization from anhydrous acetone. Thechromatographically pure product melts in the range 130°- 135° C.

The compound, the thiazolide-4-carboxylic ethyl ester of nicotinic acid,may be prepared into non-toxic pharmaceutically acceptable salts withorganic acids such as acetic, citric, tartaric, salicylic, maleic etc.or with inorganic acids such as hydrochloric and hydrobromic acid,sulfuric acid, nitric acid, and phosphoric acid.

This compound (and its salts) has been found to be activepharmacologically by reducing cholesterol, free-fatty acid andtriglyceride levels in plasma after administration.

The exact mode or situ of such activity in the organism is as yetunclear but the activity is unmistakable. An additional factor ofutility of the compounds for therapy is its low toxicity, and hightherapeutic index.

The appended examples indicate a useful simple and preferred synthesisof the novel compound, its pharmacological activity and its therapeuticactivity. The synthetic methods and the modes of administration aremerely exemplary. All art-recognized equivalent methods and materialsare intended.

EXAMPLE 1

Thiazolidide-4-carboxylic ethyl ester of nicotinic acid: (ST-61)##STR3##

Suspend 1 mole of nicotinic acid chloride hydrochloride in anhydrouschloroform, slowly and under stirring add 1 mole of the4-thiazolidinecarboxylic acid ethyl ester previously dissolved inanhydrous chloroform. The reaction vessel is equipped with a stirrer anda reflux condenser. The reaction mixture is maintained for 4 hours at25° C. with stirring. The reaction product is filtered. The chloroformsolution is evaporated to dryness then the residue is recrystallizedfrom acetone.

The melting-point of the chromatographically pure product obtained is =130°- 135° C.

The elemental analysis confirms its composition as hydrochloride.##STR4##

EXAMPLE 2 Toxicity

The compound of Example 1 (ST-61) has an LD₅₀ of 2500 mgm/kg per os inrats.

EXAMPLE 3 Pharmacological Activity

The pharmacological activity of the compound ST-61 was assessed by usingthe methods described in the following articles:

A -- The antilipolytic activity in the fasting state was studied inaccordance with

(1) Carlson L. A. and E. R. Nye, Acute Effect of Nicotinic Acid In TheRat. Plasma and liver lipids and blood glucose.

Acta Med. Scand., 179, 453, 1966.

(2) Dalton C., C. Van Trabert and J. X. Dwyer, Relationship ofNicotinamide and Nicotinic acid to Hypolipidemia, BiochemicalPharmacology, 19, 2609, 1970.

(3) Bizzi A. and S. Garattini Drugs Lowering Plasma Free Fatty Acids:Similarities and Dissimilarities with the Nicotinic acid Effect, p. 207.K. F. Gey and L. A. Carlson Edrs. Hans Huber Publisher, Bern StuttgardVienna, 1971.

B -- the antilipolytic activity in the case of Nor-Adrenaline stimulatedlipolysis in rats was investigated in accordance with

1 -- S. Garrattini and A. Bizzi Inhibiteurs de la mobilization desacides gras libres, Actualite Pharmacologiques XXII Serie, 169, 1969:

C -- the antilipolytic activity in vitro was studied in accordance with

(1) Monsigner B., M. Vanghan, Advances in Experimental Medicine andBiology Drugs affecting Lipid Metabolism, vol. 4, pag. 63 Edrs Holmes,Carlson, Paoletti Plenum Press New York 1969.

The new compound of Example 1 (ST-61) exhibited the followingpharmacological activity in the above detailed tests: (1) hypolipidemicaction: 245 mg/kg s.c. reduced the plasma levels of F.F.A. by 43 percentin the 17-h fasted rats and reduced the lipolytic activity ofsubcutaneously injected Nor-adrenaline by 65 percent in rats (FIG. 1).

36.7 mcg/ml inhibited the "in vitro" lipolytic activity of 0.15 mcg/mlof Nor-adrenaline on rat epididymal adipose tissue by 85 percent,threshold dose 5 mcg/ml (FIG. 2) and 122 mcg/ml inhibited by 97 percentthe "in vitro" F.F.A. release due to 176 mcg/ml of cyclic adenilate(FIG. 2).

The high therapeutic index of the compound was noted. ST₆₁, thethiazolidide 4-carboxylic ethyl ester of nicotinic acid clearly reduceshyperlipidaemic levels resulting from stimulated lipid mobilization andis useful in therapy where such activity is indicated as indislipidaemias.

EXAMPLE 4

The various experimental animals used in the above tests were carefullyobserved and no untoward or unusual toxic syndromes were noted in otherthan the LD₅₀ test.

The invention includes within its scope pharmaceutical preparationscontaining, as an active ingredient, the therapeutically activecompound, thiazolidide-4-carboxylic acid ester of nicotinic acid or thenon-toxic acid addition salts thereof, in association with apharmacologically acceptable carrier. Other therapeutic and compatiblematerials may be included in the preparation. The preparations may takeany of the forms customarily employed for administration oftherapeutically active substances, but the preferred types are thosesuitable for oral administration and especially tablets, pills andcapsules including the substance. The tablets and pills may beformulated in the usual manner with one or more pharmacologicallyacceptable diluents or excipients, for example lactose or starch, andinclude materials of a lubricating nature, for example calcium stearate.Capsules made of absorbable material, such as gelatin, may contain theactive substance alone or in admixture with a solid or liquid diluent.Liquid preparations may be in the form of suspensions, emulsions, syrupsor elixirs of the active substance in water or other liquid mediacommonly used for making orally acceptable pharmaceutical formulations,such as liquid paraffin, or a syrup or elixir base. The active substancemay also be provided when indicated, in a form suitable for parenteraladministration, i.e. as a suspension or emulsion in sterile water or anorganic liquid usually employed for injectable preparations, for examplea vegetable oil such as olive oil, or a sterile solution in an organicsolvent.

The following Examples illustrates the preparation of a pharmaceuticalcomposition according to the invention.

EXAMPLE 5

25 g of thiazolidide-4-carboxylic ethyl ester of nicotinic acid 25 g ofAvicel PH 101 (microcrystalline cellulose) and 25 g of Aerosil (highlypurified silicon dioxide) are mixed together and gelatin capsules arefilled each with the mixture so that each capsule contains 10 mg ofactive substance.

EXAMPLE 6

800 g of lactose and 200 g of maize starch are mixed with 200 ml of 5%maize starch in water. The mixture is granulated, dried at 55° C. andsieved through a No. IV sieve (Sieve opening 0.7 mm). 1000 g of thegranulate are mixed with 100 g of thiazolidide-4-carboxylic ethyl esterof nicotinic acid and gelatin capsules are filled each with the mixtureso that each capsule contains 10 mg of the active substance.

What is claimed:
 1. The compound: Thiazolidide-4-carboxylic ethyl esterof nicotinic acid having the formula: ##STR5## and the non-toxic,pharmacologically acceptable salts thereof.